Combination therapy with lithium and valproate is more likely to prevent relapse in patients with bipolar disorder than valproate monotherapy, researchers say.

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Explain that combination therapy with lithium and valproate is more likely to prevent relapse in patients with bipolar disorder than valproate monotherapy, but there's no evidence it's better than lithium monotherapy.

Combination therapy with lithium and valproate is more likely to prevent relapse in patients with bipolar disorder than valproate monotherapy, researchers say.

However, there appeared to be no advantage for combination therapy over lithium monotherapy, John R. Geddes, MD, of the University of Oxford, and colleagues reported online in The Lancet.

"For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy," the researchers wrote.

But the study "could neither reliably conﬁrm nor refute a beneﬁt of combination therapy compared with lithium monotherapy," they concluded.

Major shifts away from prescription of lithium have occurred, despite a lack of good comparative evidence, the researchers said. And prescriptions of valproate have risen, with a combination of these two drugs prescribed if patients are not responsive to initial monotherapy.

They assessed 330 patients ages 16 and older who had the disease at 41 sites in the U.K., the U.S., France, and Italy. They were randomly assigned to open-label lithium monotherapy, valproate monotherapy, or both agents in combination, after an active run-in of four to eight weeks on combination therapy.

The study was not blinded, and patients were followed for up to 24 months. The primary outcome was the initiation of a new intervention for an emergent mood episode.

A total of 54% of those in the combination therapy group had a primary outcome event during follow-up, compared with 59% of patients in the lithium group and 69% of those taking valproate.

"The hazard ratio of the primary outcome was significantly lower for participants allocated to combination therapy than for those allocated to valproate monotherapy, but not lower than for those allocated to lithium monotherapy," the researchers wrote.

There was a 15.5% difference in risk between combination therapy and valproate monotherapy, which translated to a number needed to treat of seven.

A 10% difference between valproate and lithium monotherapies translated to a number needed to treat of 10, while a nonsignificant 5.5% difference between combination therapy and lithium monotherapy amounted to a number needed to treat of 19.

"The unequivocal and substantial effect of adding lithium to valproate is striking and could be even larger in highly adherent patients with optimum therapy," the researchers wrote.

The researchers noted that the adjusted risk of hospital admission for patients on combination therapy was significantly lower than for patients on valproate.

There were seven serious adverse events in the valproate group, five in the lithium group, and four in the combination therapy group. Among these, there were three, two, and one deaths in each group, respectively.

The authors noted that the study was limited because treatment allocation could not be masked from either the investigators nor the participants.

In terms of clinical recommendations, the researchers said that patients would do better with first-line combination therapy than the currently recommended valproate monotherapy.

Also, patients who have frequent relapses during treatment with lithium monotherapy could switch to the combination, rather than valproate as currently recommended.

"The BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment," Rasmus W. Licht, MD, of Aarhus University Hospital in Denmark, wrote in an accompanying editorial.

"However, the suggestion that emerging nonresponders to long-term lithium treatment should be continued on lithium combined with valproate is debatable. The combination could be better than lithium alone ... [but] many clinicians might prefer an alternative strategy involving neither lithium nor valproate, in view of the potential long-term renal side effects of lithium."

Licht wrote that the trial also confirms the long-term efficacy of lithium "not only for the prevention of mania, but also for prevention of depression."

The study was supported by Stanley Medical Research Institute and sanofi-aventis.

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